Aurora-A-mediated phosphorylation of LKB1 compromises LKB1/AMPK signaling axis to facilitate NSCLC growth and migration

作者：Zheng, X.; Chi, J.; Zhi, J.; Zhang, H.; Yue, D.; Zhao, J.; Li, D.; Li, Y.; Gao, M.^*; Guo, J.^*

来源：Oncogene, 2018, 37(4): 502-511.

DOI：10.1038/onc.2017.354

• CELL LUNG-CANCER
• TUMOR-SUPPRESSOR LKB1
• EML4-ALK FUSION GENE
• KINASE INHIBITOR
• POOR-PROGNOSIS
• BREAST-CANCER
• ENERGY STRESS
• LKB1-STRAD-MO25 COMPLEX
• PROSTATE-CANCER
• AMPK ACTIVITY

Deletion or loss-of-function mutation of LKB1, frequently occurring in non-small cell lung cancers (NSCLCs), is a predominant caution of NSCLC initiation and progression. However, the upstream signaling pathways governing LKB1 activation are largely unknown. Here, we report that LKB1 undergoes Aurora kinase A (AURKA)-mediated phosphorylation, which largely compromises the LKB1/AMPK signaling axis, in turn leading to the elevation of NSCLC cell proliferation, invasion and migration. Mechanically, AURKA-mediated phosphorylation of LKB1 impairs LKB1 interaction with and phosphorylation of its downstream target AMPKa, which has critical roles in governing cancer cell energy metabolic homeostasis and tumorigenesis. Clinically, AURKA displays high levels in NSCLC patients, and correlates with poor outcome of patients with lung adenocarcinoma. Pathologically, the amplification or activation of AURKA-induced impairment of the LKB1/AMPK signaling pathway contributes to NSCLC initiation and progression, highlighting AURKA as a potential therapeutic target for combatting hyperactive AURKA-driven NSCLCs.

• 出版日期2018-1-25
• 单位天津医科大学